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A novel tumor suppressor encoded by a 1p36.3 lncRNA functions as a phosphoinositide-binding protein repressing AKT phosphorylation/activation and promoting autophagy

Cell Death & Differentiation volume 30, pages 1166–1183 (2023)Cite this article

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Abstract

Peptides/small proteins, encoded by noncanonical open reading frames (ORF) of previously claimed non-coding RNAs, have recently been recognized possessing important biological functions, but largely uncharacterized. 1p36 is an important tumor suppressor gene (TSG) locus frequently deleted in multiple cancers, with critical TSGs like TP73, PRDM16, and CHD5 already validated. Our CpG methylome analysis identified a silenced 1p36.3 gene KIAA0495, previously thought coding long non-coding RNA. We found that the open reading frame 2 of KIAA0495 is actually protein-coding and translating, encoding a small protein SP0495. KIAA0495 transcript is broadly expressed in multiple normal tissues, but frequently silenced by promoter CpG methylation in multiple tumor cell lines and primary tumors including colorectal, esophageal and breast cancers. Its downregulation/methylation is associated with poor survival of cancer patients. SP0495 induces tumor cell apoptosis, cell cycle arrest, senescence and autophagy, and inhibits tumor cell growth in vitro and in vivo. Mechanistically, SP0495 binds to phosphoinositides (PtdIns(3)P, PtdIns(3,5)P2) as a lipid-binding protein, inhibits AKT phosphorylation and its downstream signaling, and further represses oncogenic AKT/mTOR, NF-κB, and Wnt/β-catenin signaling. SP0495 also regulates the stability of autophagy regulators BECN1 and SQSTM1/p62 through modulating phosphoinositides turnover and autophagic/proteasomal degradation. Thus, we discovered and validated a 1p36.3 small protein SP0495, functioning as a novel tumor suppressor regulating AKT signaling activation and autophagy as a phosphoinositide-binding protein, being frequently inactivated by promoter methylation in multiple tumors as a potential biomarker.

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Fig. 1: Epigenomic identification of KIAA0495 as a novel 1p36.3 TSG candidate.
Fig. 2: KIAA0495 encodes a small protein SP0495.
Fig. 3: Promoter CpG methylation silences KIAA0495 in multiple tumors.
Fig. 4: SP0495 is a functional tumor suppressor in carcinoma cells.
Fig. 5: SP0495 inhibits AKT/mTOR, Wnt/β-catenin and NF-kB signaling pathways.
Fig. 6: Ectopic expression of SP0495 induces autophagy in carcinoma cells.
Fig. 7: SP0495 regulates BECN1 and p62 stability and their ubiquitination in carcinoma cells.
Fig. 8: SP0495 binds to phosphoinositides with a preference for PI3P and PI(3,5)P2.

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Acknowledgements

We thank Drs B Vogelstein, G Srivastava, GSW Tsao, Sun Young Rha, the late Dolly Huang and KT Yao for cell lines; DSMZ (Germany) for KYSE cell lines (Shimada et al., Cancer 69: 277–284 (1992); Kazusa DNA Research Institute for the full-length clone of KIAA0495; Drs Christof Niehrs and Dong-Yan Jin for TOPFlash and FOPFlash constructs; Dr. Ben CB Ko for autophagy assay, and FanFong Poon for some technical support.

Funding

This study was supported by HK-RGC (#14115019; #14115920; #14102923), NSFC (#81772869), China MOST National Key Research and Development Program (#2017YFE0191700), and Johns Hopkins Singapore/A*STAR.

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Authors and Affiliations

  1. Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong

    Lili Li, Xing-sheng Shu, Hua Geng, Jianming Ying, Jie Luo, Longtao Wu, Brigette B. Y. Ma, Anthony T. C. Chan & Qian Tao

  2. School of Medicine, Shenzhen University Health Science Center, Shenzhen, China

    Xing-sheng Shu

  3. Department of Pathology, Cancer Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China

    Jianming Ying & Lei Guo

  4. The First Affiliated Hospital of Chongqing Medical University, Chongqing, China

    Tingxiu Xiang

  5. Chongqing University Cancer Hospital, Chongqing, China

    Tingxiu Xiang

  6. State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China

    Xiaofeng Zhu

  7. Johns Hopkins Singapore and Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Richard F. Ambinder & Qian Tao

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  1. Lili Li
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Contributions

QT, LL: conceptual design; LL, XS, HG, JY, LG, JL, TX, LW: performed experiments; BBM, ATC, XZ, RFA: provided materials and reviewed manuscript; LL, XS, HG, QT: drafted the manuscript; LL, QT: finalized the manuscript.

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Correspondence to Lili Li or Qian Tao.

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Li, L., Shu, Xs., Geng, H. et al. A novel tumor suppressor encoded by a 1p36.3 lncRNA functions as a phosphoinositide-binding protein repressing AKT phosphorylation/activation and promoting autophagy. Cell Death Differ 30, 1166–1183 (2023). https://doi.org/10.1038/s41418-023-01129-w

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